AU2016311502B2

AU2016311502B2 - Compositions for app-selective bace inhibition and uses therfor

Info

Publication number: AU2016311502B2
Application number: AU2016311502A
Authority: AU
Inventors: Dale Bredesen; Oleksandr Buzko; Barbara Jagodzinska; Varghese John; Patricia SPILMAN
Original assignee: Nantneuro LLC
Current assignee: Nantneuro LLC
Priority date: 2015-08-27
Filing date: 2016-08-29
Publication date: 2019-07-18
Anticipated expiration: 2036-08-29
Also published as: CA2996542A1; CA2996542C; US11142505B2; KR20180090778A; WO2017035529A9; US20190077766A1; JP2021001188A; AU2016311502A1; JP2018525447A; EP3341362B1; EP3341362A4; EP3341362A1; WO2017035529A1; CN108349905A; CA3096896A1

Abstract

Selected compounds, compositions, and methods for inhibiting BACE are presented that have relatively high selectivity towards APP via interaction of the inhibitor with both BACE and APP.

Description

COMPOSITIONS FOR APP-SELECTIVE BACE EXHIBITION AND USES

THERFOR [0001] This claims priority to our US provisional application, having serial number 62/210945, winch was fifed 27-Aug-I5 and which is incorporated by reference herein,

Field of The Invention [0002] The field of the invention is enzyme inhibitors and methods therefor, particularly as it relates to APP (amyloid precursor protein)-specific BACE (beta-secretase) inhibitors.

Background of the Invention [0003] fhe background description includes information that may be usefill in understanding the present invention. It is not an admission that any of the informa tion provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0005] BACE inhibitors have gained significant attention due to the discovery that a mutation in die APP appears to protect against Alzheimer s Disease and oilier age-related cognitive decline. More specifically, the mutation is at the P2’ residue of the BACE cleavage site and results in a significantly reduced Αβ production. Unfortunately, the substrate specificity of BACE is not exclusively limited to APP, and complete inhibition of BACE would thus have 25 adverse effects.

[0006] More recently, certain B ACE inhibitors with at feast some selectivity towards BACE were reported as is disclosed in WO 2014/127042. US 2016/0159746. and US 2014/0371283. While such inhibitors had desirable selectivity against RACE wi th respec t to APP, relatively high coucentrations were required for inhibition. Moreover., many of the compounds failed to 30 penetrate the blood brain barrier.

2016311502 15 Apr 2019 [0007] Thus, despite the relatively detailed knowledge of BACE activity and its substrate APP, various drawbacks still remain for known BACE inhibitors, especially high IC50 and/or lack of penetrability across the blood brain barrier. Therefore, there is still a need to provide improved BACE inhibitors and methods.

Summary of the Invention [0008] The present inventive subject matter is drawn to various compounds, compositions, and methods of BACE inhibition, and particularly to compounds and compositions that interact with both BACE and APP to so increase selectivity of the inhibitor. Moreover, compounds presented herein exhibit desirably low IC50 values and penetrability across the blood brain barrier.

[0008A] In a first aspect, the present invention provides compound having a structure according to Formula I:

wherein Ri is a halogenated heteroaryl;

R2 is an optionally halogenated lower alkoxy group or an optionally halogenated Nalkylamino group; and

R₃ is H, halogen, or optionally halogenated lower alkyl.

[0008B] In a second aspect, the present invention provides_a_compound having a structure according to Formula II:

2016311502 15 Apr 2019

wherein R2 is an optionally halogenated lower alkoxy group or an optionally halogenated Nalkylamino group;

R3 is H, halogen, or optionally halogenated lower alkyl; and

R4 is an oxazolyl.

[0008C] In a third aspect, the present invention provides a compound having a structure according to Formula IV:

[0008D] In a fourth aspect, the present invention provides a compound having a structure according to Formula V:

2a

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[0008E] In a fifth aspect, the present invention provides a compound having a structure according to Formula VI or XIII:

Formula XIII.

[0008F] In a sixth aspect, the present invention provides a compound having a structure according to Formula VII:

2b

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Formula VII.

[0008G] In a seventh aspect, the present invention provides a compound having a structure according to Formula VIII:

Formula VIII.

[0008H] In an eighth aspect, the present invention provides a compound having a structure according to Formula IX:

2c

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Formula IX.

[00081] In a ninth aspect, the present invention provides a compound having a structure according to Formula X:

Formula X.

[0008J] In a tenth aspect, the present invention provides a compound having a structure according to Formula XI:

2d

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Formula XI.

[0008K] In an eleventh aspect, the present invention provides a compound having a structure according to Formula XII:

Formula XII.

[0008L] In a twelfth aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect in combination with a pharmaceutically acceptable carrier.

[0008M] In a thirteenth aspect, the present invention provides use of a compound according to the first aspect in the manufacture of a medicament.

[0008N] In a fourteenth aspect, the present invention provides use of a compound according to the first aspect for the treatment of Alzheimer’s Disease.

2e [00080] In a fifteenth aspect, the present invention provides a method of treating a patient diagnosed with Alzheimer’s Disease or at risk for disease progression of mild cognitive decline, comprising a step of administering to the patient in need thereof a pharmaceutical composition comprising a compound according to first aspect in an amount effective to treat the patient.

[0008P] In a sixteenth aspect, the present invention provides a method of reducing BACE activity, comprising contacting BACE with a compound according to the first aspect.

[0009] Described herein is a compound that has a structure according to Formula I

2016311502 15 Apr 2019

Formula I wherein Ri is phenyl substituted with (i) an alkoxyalkyl, (ii) an N-alkylalkyl, or (iii) a optionally halogenated heteroaryl (e.g., pyridinyl, pyrimidinyl, or oxazolyl), or wherein Ri is a halogenated heteroaryl. R2 is preferably an optionally halogenated lower alkoxy group (e.g., difluoromethoxy group) or an optionally halogenated Nalkylamino group, and R3 is most preferably H, halogen, or optionally halogenated lower alkyl. Therefore, suitable compounds may have a structure according to Formula II or III

2f

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Formula U

CH,

I '

Formula III wherein R₂ and R3 are as defined above, and wherein R4 is an optionally halogenated pyridinyl, pyrimidmyl, or oxazolyi, and wherein R4 is halogen (e.g., F). In especially preferred aspects, the compounds will have a structure according to any one of Formulae IVXII

Formula IV

Formula VI

Formula VII ,7

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Formula XU [0010] Consequently, the inventors also contemplate a pharmaceutical composition comprising a compound contemplated herein in combination with a pharmaceutically acceptable earner. Most typically, the compound will be present in an amount effective to inhibit BACE in a patient when administered (e.g., orally or via injection) to the patient. As will be readily appreciated, as uch formulations have BACE inhibitory activity, they will be

WO 2017/035529

PCT/US2016/049271 suitable (aloue or in combination with another pharmaceutical agent) for treatment of a neur ological condition, and particularly for treatment of Alzheimer’s Disease.

[0011] Viewed, from another perspective, the iriventois also contemplate the use of contemplated compounds in. the manufacture of a medicament especially where the medrcamerr i is used in the trea hnent of a neuradegerrera live disease, and/or where the medicament is for the reduction of selective BACE activity in a patient, t/onsequently, BACE inhibitors and uses thereof are also specifically contemplated herein and particularly include treatment of neurological conditions (e.g., Alzheimer’s Disease). Thus, the inventors also contemplate treating a patient diagnosed with Alzheimer’s Disease or at risk for disease progression of mild cognitive decline.

[0012] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

Brief Description of The Drawing [0013] Figure 1A depicts exemplary compounds according to the inventive subject matter, and Figures IB-ID depict exemplary test results for selected compounds.

[0014] Figure 2A depicts an exemplary compound according to the inventive subject matter, and Figures 2B-2C depict exemplary test results for selected compounds.

[0015] Figure 3A depicts exemplary compounds according to the inventive subject matter, and Figures 3B-3E depict exemplary test results for selected compounds.

[0016] Figure 4 depicts exemplary pharmacokinetic test results for selected compounds.

[0017] Figure 5A depicts an exemplary compound according to the inventive subject matter·, and Figures 5B-5C depict exemplary test results for the compound of Figure 5A.

[0018] Figure 6A depicts an exemplary compound according to the inventive subject matter', and Figure 6B depicts exemplary test results for the compound of Figure 6 A.

[0019] Figure 7A depicts an exemplary compound according to the inventive subject matter, arid Figure 7B depicts exemplary test r esults for the compound of Figure 7 A.

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PCT/US2016/049271 [002Q] Figure 8 depicts an exemplary compound according to the inventive subject matter and an exemplary test results for the exemplary compound.

Detailed Description [0021] The invenfol's have discovered that certain compounds as further described in more detail below had improved parameters with respect, to BA.CE inhibition. Most notably, several of these compounds also exhibited penetrance across the blood brain barrier and preferentially inhibited BACE with respect to APP as substrate.

[0022] The improved BACE inhibitors as contemplated herein will generally have a structure according to Formula I

Formula I wherein Rj is typically a substituted aryl or heteroaryl group, and most preferably a phenyl substituted with (i) an alkoxyalkyl, (ii) an N-alkylalkyl, or (iii) an optionally halogenated heteroaryl, or R_} is a halogenated heteroaryl. In birther preferred aspects, R₂ is an optionally 15 halogenated lower alkoxy group (typically having 1 -3 carbon atoms), an optionally halogenated N-alkylamino group (typically having 1-3 carbon atoms), an OH group, a CN gr oup, etc. In still birther preferred aspects, R₃ will be H, a halogen, or an optionally halogenated lower alkyl (typically having 1-3 carbon atoms).

[0023] For example, wherein R; is a phenyl, it is preferred that the phenyl is substituted with a radical that includes a heteroatom, and most preferably an oxygen or nitrogen that is separated from the phenyl by one carbon atom. Among other suitable radicals it is therefore contemplated that the phenyl may be substituted with an alkoxyalkyl (e,g., mefhoxyrnethyi) group or a N-alkylalkyl (N-methyl methyl) group. Alternatively, the phenyl in R_{ may also be substituted with an optionally halogenated heteroaryl. While numerous heteraml gr oups are deemed suitable, especially preferred heteioaryl groups will be five- or six-membered ring

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PCT/US2016/049271 systems with one or two heteroatoms (e.g;, N and/or O). Consequently, suitable heteroaryl groups include pj-ridinyl, pyrimidinyl, and oxazolyl groups.

[0024] In further contemplated aspects, RI may also be a halogenated, heteroaryl. Most typically, the heteroaryl will be a five* or six-membered ring and include one, two, or three lieteroatoms. For example, suitable heteroaryl rings include imidazole, pyridine, pyrimidine, etc. With respect to the halogen substituent it is generally preferred that the halogen is fluorine or chlorine, and most typically- fluorine.

[0025] R2 in most preferred compounds will be a halogenated alkoxy group, and most typically will have 1-3 carbon atoms. For example, especially preferred R2 groups will be a halogenated methoxy group, and especially a fluoromethoxy·, difhiorornethoxy, or trifluoromethoxy group. Alternatively, R2 may also be a relatively small substituent, including halogens, a methyl group, a CN group, or hydrogen. likewise, R3 is preferably a relatively small substituent and may be hydrogen, lower alkyl (between 1-3 carbon atoms), CN, or a halogen.

[0026] Therefore, in further contemplated aspects of tire inventive subject matter, contemplated compounds may also have a structure according to Formula II

Formula II wherein R₂ is an optionally halogenated lower alkoxy gr oup as descr ibed above or an optionally halogenated N-alkylamino group as described above. For example, an especially preferred R? group includes a halogenated methoxy group, particularly a difluoromethoxy gr oup. Similarly, it is preferred that R₃ may be a hydrogen, a halogen (and especially fluorine or chlorine), or an optionally halogenated lower alkyl as described above. In further preferred compounds, R$ is an optionally halogenated pyridinyl, pyrimidinyl, or oxazolyl.

Where Ri is halogenated, it is typically preferred that tire halogen radical is a fluorine or

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PCT/US2016/049271 chlorine radical Moreover, it should be noted that while a single halogen is generally preferred, two, three, or more halogens are also expressly contemplated.

[0027] 'Where Ry of Formula I is a heteroaryl, it is generally preferred that the heteroaryl will comprise one or two heteroatoms (preferably nitrogen and/or oxygen), arid that the heteroaryl 5 is a five- or six-membered ring. Particularly preferred compounds will therefore have a structure according to Formula IH

CH..

Formula III in which R? is an optionally halogenated lower alkoxy group <Xg., difluoromethoxy group) or 10 an optionally halogenated N-alkylamino group as already described above. With respect to

Rs it is generally contemplated that this R₃ is H. halogen, or an optionally halogenated lower alkyl (e.g., optionally fluorinated methyl). R₅ is a halogen, and most typically a fluorine or chlorine radical. Moreover, it is noted that the heteroaryl may be further halogenated with one or more additional halogen radicate. In the compomid of Formula HL X and Q are typically independently CH or N, and X and Q are not the same. However, one or more other heteroatoms (including S and Se) are also expressly contemplated.

[0028] Consequently, especially preferred compounds according to the inventive subject matter will include those shown below having a structure according to Formulae IV-XHI

S

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Formula V

Formula IV

OH_S

Formula VII

Formula VI

Formula VIII

Formula X

Formula XI

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[0029] hi further contemplated aspects, it is noted the compounds according to Formulae IXIII may include aryl or heteroaryl groups other than those specified above, and suitable alternative aryl or heteroaryl groups include aromatic monocyclic or polycyclic groups, typically comprising between 5 and 18 carbon ring members, which may be unsubsti toted or substituted by one or more suitable substituents, and which may be further fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaiyl groups (which themselves may be unsubstituted or substituted by one or more suitable substituents). Examples for aryl groups include phenyl, biphenyl, 1,2,3,4-tetrahydronaphtIiyI, naphthyl, anthryl, and phenanthryl. Suitable heteroaryl groups will typically include aromatic monocyclic or polycyclic groups comprising generally between 4 and 18 ring members, including 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Examplary heteroaryl gropus include thienyl, furanyl, thiazolyl, triazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tefrazolyl, pyridyl, pyrrolyl, thiadiazolyl, oxadiazolyl, oxafhiadiazolyl, thiatriazolyl, pyrimidinyl, isoquinolinyl, quiuolinyl, napthyridinyi, phthalhnidyi, benzimidazolyl, and benzoxazolyt [0030] In general, the various moieties or functional groups for variables in the formulae may be substituted by one or more suitable substituents. Hie term ’’substituent or is intended to mean any suitable substituent that may be recognized or selected, by those skilled in tire art. Illustrative examples of useful substituents are those found in the exemplary compounds that follow, as well as halogen (chloro, iodo, bromo, or fluoro); Cj^-alkyl; Cj-g-alkenyl; Ci_6

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PCT/US2016/049271 alkynyl; hydroxyl; C« alkoxyl; amino; mfrp; thiol; thioethei·; inline; cyano; amido; phosphonato; phosphine; carboxyl; emboayl; ammucarbonyl; thiocarbonyl; sulfonyl; sulforrarnhie; sulfanamide; ketone; aldehyde; ester, oxygen .(=€>); haloalkyl (e.g., triiluoromefhyl); carbocyclic cyeloalkyl, which may be monocyclic or fused or non-fiised polycyclic («7,g., cyclopropyl, cyclobtityl, cyeiopentyL or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fosed polycyclic (e g., pyrrolidinyl, piperidinyl, piperazhiyl, morpholmyl, Or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fiised polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, feranyl, thiophenyl, imidazolyl, oxazolyi, isoxazolyl, thiazolyl, triazolyl, tetiazolyl, pyrazolyi, pyridinyl, quinolinyl, isoquinolniyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); ammo (primary, secondary, or tertiary); miro; thiol; thioether, O-lower alkyl; O-aryl, aryl; aryl-lower alkyd; CO2CH3; CONH2; OCH2CONH2; NHz; SO2NH2; OCHF2; CFj; OCF3; and the like. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCHi-O.

[0031] All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cyeloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, alkylamino groups, dialkylainirio groups, carbamoyl groups, aryloxyl groups, heteroaryioxyl groups, arylthro groups, heteroarylthio groups, and the like. The term optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (eg., by indicating that the specified group is unsubstituted).

Furthermore it should be noted that the compounds contemplated herein may be prepared as prodiugs. The term prodnig as used herein refers to a modification of contemplated compounds, wherein the modified compound exhibits less pharmacological activity (as compared to tire modified compound) and wherein tire modified compound is converted witliia a target cell (g,g., B-cell) or target orgaii/anatomic structure (e.g., joint) back into the modified form. For example, conver sion of contemplated compounds into prodrags may be useful where the active drug is too toxic for safe systemic administration, or where the

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PCT/US2016/049271 contemplated compound is poorly absorbed by the digestive tract or other compartment or cell, or where tire body breaks down tire contemplated compound before reaching its target. Ulus, it should be recognized that the compounds according to the inventive subject mater' can be modified in numerous manners, and especially preferred modifications include those that improve one or more pharmacokinetic and/or phrnmacedynamic parameter. For example, one or more substituents may be added or replaced to achieve a higher AUC in serum, [0032] On the other hand, and especially where increased solubility is desired, hydrophilic groups may be added. Still further, wher e contemplated compounds contain one or more bonds that can be hydrolyzed (or otherwise cleaved), reaction products are also expressly contemplated. Exemplary suitable protocols for conversion of contemplated compounds into the corresponding prodrag form can be found in Prodrags (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monogr aphs)” by Kenneth B . Sloan (ISBN: 0824786297), and Hydrolysis in Drag and Prodrug Metabolism: Chemistry, Biochemistry⁷, and Enzymology by Bernard Testa, Joadiim M. Mayer (ISBN: 390639025X), both of which are incorporated by reference herein. Moreover, especially where contemplated compounds have a higher activity when the compound is metabolized (e.g.., hydrolyzed, hydroxylated, glucuronidated, etc.), it should be appreciated that metabolites of contemplated compounds are also expressly contemplated herein.

[0033] Of course, it should be appreciated that (where appropriate) contemplated compounds may have one or more asymmetric centers or groups that may give rise to isomeric, tautomeric, or other steric isoforms (e.g., R-, and/or S-configuration, E/Z configuration, tautomeric isoforms, enantiomer’s, diastereomers, etc,), and each of such forms and mixtures thereof ar e expressly contemplated herein.

[0034] hi further contemplated aspects, the compounds may be formulated into a pharmaceutical composition, typically in combination with a pharmaceutically acceptable carrier. Preferably, the compound will be present at a concentration effective to treat Alzheimer’s Disease or signs and/or symptoms associated with Alzheimer’s Disease. Viewed from another perspective, it is also contemplated that the compounds will be present in the pharmaceutical composition in an amount effective to reduce BACE activity in a patient when the formulation is administered to fire patient. Therefore, contemplated compounds and pharmaceutical compositions will also be advantageous in reducing Αβ level in neuronal tissue and associated plaque build-up.

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PCT/US2016/049271 [0035] Depending on the structure of contemplated compounds, it is therefore contemplated that the compounds according to the inventive subject matter are present in the composition m an amount between 1 micr ogram to 1000 milligram, more typically between .10 microgram to 500 milligram, and most typically between 50 microgram to 500 milligram per single dosage unit. Thus, preferred concentrations of contemplated compounds Μ wo or in vitro. will generally be between 0.1 rrM and SOOmieroM, more typically between 50 nM arid 400 microM, .and most typically between 100 nM and 200 microM. Consequently, in. vivo concentrations will generally be suitable to reduce BACE activity in vivo with respect to APP cleavage by at least 10%, and more typically by at least 25%.

[0036] Furthermore, it should be recognized that all formulations are deemed suitable for use herein and especially include oral and parenteral formulations. For example, for oral administration, contemplated compositions may be in the fonri of a tablet, capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextr ose or water may be used as a suitable carrier. Furthermore, where the compound is formulated for intrathecal administration, it is generally piefened that the compound is prepar ed as ari injectable solution, suspension, or emulsion, hr still further contemplated formulations, contemplated compounds may be formulated for aerosol delivery (e.g., micropowderized, coated onto a dispersible carrier, dissolved hi atomizable solvent, etc.) [0037] It should be appreciated that the choice of the particular formulation and carrier will at least in part depend on the specific use and type of compound. There are numerous maimers of drug formulation known hr the art, and all of those ar e deemed suitable for use herein (see

e.g., Pharmaceutical Prefonnulation and Formulation: A Practical Guide from Candidate

Drug Selection to Commercial Dosage Form by Mark Gibson; hifonua HealthCare, ISBN: 1574911201; or Advanced Drug Formulation Design to Optimize Therapeutic Outcomes by Robert O. Williams, David R. Taft, and Jason T. McConville; Informa HealthCare; ISBN: 1420043870).

[0038] Tire amount, of therapeutically active compound that is administered arid the dosage r egimen for tr eating a disease condition with the compounds audfor compositions of this invention depends on a variety of factors, including the age, weight, sex and medical

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PCT/US2016/049271 condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. However, especially suitable quantities are provided above, and may therefore allow for a daily dose of about 0.00’1 (or even less) to 100 mg/kg body weight, preferably between about 0.01 arid about 50 mg/kg body weight and most preferably from about 0.1 to 20 mg/kg· body weight. Typically, a daily dose can be administered in one to four doses per day, [0039] For therapeutic or prophylactic purposes, contemplated compounds are ordinarily combined with one or more excipients appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a coritrolled-release formulation as may be provided in a dispersion of active compound in hyAoxypi'opyl-methyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration . The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other excipients and modes of administration are well and widely known in the pharmaceutical art.

[0040] Additionally, it is contemplated that contemplated compounds may be combined (m vivo or in a pharmaceutical formulation or administr ation regimen) with another pharmaceutically active ingredient, and especially contemplated other ingredients include various drags tar geting amyloid plaque, tau hyperphosphorylation, various hnmmiomodulatory drugs, and/or anti-inflammatory drags (e.g., steroids and NSAIDS), etc. Concentrations of second pharmaceutically active ingredients are typically at or preferably below those recommended for stand-alone administration, however, higher concentrations are also deemed suitable for use herein.

[0041] Preferably, contemplated compounds will have an IC50 (with respect to BACE inhibition arid APP as substrate) of equal or less than 10 μΜ, more preferably of equal or less

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PCT/US2016/049271 than I μΜ, and most preferably of equal or less than 100 ήΜ, and will have no apparent toxicity at the IC50 as measured above. Once candidate compounds (typically having IC& of equal or less than 1.0 pM, more typically equal or less than 0.1 pM, and mositypically equal or less than 0.01. phi ) are identified, such compounds can be further modified to ascertain 'SAR and to produce compounds with higher potency, reduced toxicity·, and/or increased bioavailability. Therefore, particularly preferred compormds not only include those as shown in Formulae Ι-ΧΣΠ. above, but also include those of Tables 1-4 below.

Experimental Data and Results [0042] Synthetic Protocols:

[0043] Contemplated compounds can be prepared using various methods known in the art, and all of those are deemed suitable for use herein. Further particularly suitable methods will follow the generally synthetic protocol as described in US' .2014/0371283 with slight modifications to accommodate various substituents, |0044] Assay Systems to Evaluate APP Processing: Without being bound to a particular theory, it is believed that the active agent(s) described, herein promote processing of APP by the nonamyloidogenic pathway and/or reduce or inhibit processing of APP by the amyioidogenic pathway. In the nonamyloidogeic pathway, APP is first cleaved by a-secretase within the Αβ sequence, releasing the APPsa ectodomain (“sAPPu”), In contrast, the amyioidogenic pathway is initiated when β-secretase cleaves APP at the amino terminus of the Αβ, thereby releasing the APPsp ectodomain (“sAPPp”).

[0045] One method to evaluate the efficacy of the active agent(s) is to determine a reduction or elimination in the level of APP processing by the amyioidogenic pathway, e.g., a reduction or elimination in the level of APP processing by β-secretase cleavage in response to tire administration of the agent(s) of interest. Assays for determining the extent of APP cleavage at the β-secretase cleavage site are well known in the art. Illustrative assays are described, for example, in U.S, Pat, Nos. 5,744,346 and 5,942,400. Kits for determining the presence and levels in a biological sample of sAPPct and sAPPp, as well as APPneo and Αβ commercially available, e.g., from PerkinElmer.

[0046] ABBI Assay: APP Binding BACE Inhibitor (ABBI) activity of any of the compounds described herein can readily be verified using, for example, assays described herein.

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Basically, in certain embodiments a pair the assays are utilized to identify ABBI compounds that inhibit BACE cleavage of the MBP-C125 APP substrate, resulting in the inhibition of the psoductiou of C'99 and the β-siie pep:ide substrafe (P5-P5^!'; and also mtaaets mih APP. for example, as measured by surface plasmon resonance (SPR) analysis.

[0047] In one illustrative embodiment, an MBP-C125 APP695 wt fusion protein can be used as one of the substrates and the second substrate can be tire commercially available P5-P5' fluorescence substrate. Each of these substrates is incubated with recombinant BACE (R&D (cat#931-AS-O5O) in, for example, a 96 well plate format. For the MBP-C125 substrate the C-99 product from the BACE cleavage can be measured using an AlphaLisa assay as a readout. For the P5-5' substrate, the loss of fluorescence upon BACE cleavage can be used as the readout. For the SPR assay the binding analysis of contemplated compounds to fragments of the ectodomain of APP (eAPP) that are recombmanfly prepared (see eg., Libeu et al (2012) PLoS ONE 7(6): e40027) would be done. An ABBI would inhibit the BACE cleavage of the MBP-C 125 and/or the fluorescence substrate and would also bind to the ectodomain of 15 APP such as the APP230-624 fragment.

[0048] Other' Cell Free Assays: Illustrative assays that can be used to demonstrate the inhibitory activity of the active agent(s) are described, for example, in WO 2000/017369, WO 2000/0003819, and US 5,942,400 and 5,744,346. Such assays can be performed in cell-free incubations or in cellular incubations using cells expressing an alpha-secretase and/or beta20 secretase and an APP substrate having a alpha-secretase and beta-secretase cleavage sites.

[0049] In further aspects of the inventive subject matter, contemplated compounds are contacted with an APP substrate containing alpha-secretase and beta-secretase cleavage sites of APP, for example, a complete APP or variant, an APP fragment, or a recombinant or synthetic APP substrate containing the amino acid sequence: KM-DA or NL-DA (APP-SW), 25 is incuba ted in the presence of an alpha-secretase and/or beta-secretase enzyme, a fra gment thereof, or a synthetic or recombinant polypeptide variant having alpha -secretase or betasecretase activity and effective to cleave the alpha-secretase or beta-secretase cleavage sites of APP, under' incubation conditions suitable for the cleavage activity of the enzyme.

Agerit(s) having the desired activity reduce or prevent cleavage of the APP substrate. Suitable 30 substrates optionally include derivatives that may be fusion proteins or peptides that contain the substrate peptide and a modification useful to facilitate the purification or detection of the peptide or its alpha-secretase andtor beta-secretase cleavage products. Usefill modifications

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PCT/US2016/049271 include the insertion of a known autigenic epitope for antibody binding; the linking of a label or detectable moiety, the linking of a binding substrate, and the like.

[005Q| Suitable incubation conditions for a cell-free in vitro assay include, for example: approximately 200 riM to 10 p.M substrate, approximately 10 to 200 pM enzyme, and approximately 0.1 nM to 10 μΜ of the agent(s), in aqueous solution, at an approximate pH of 4-7, at approximately 37“ C., tor a time period of approximately 10 minutes to 3 hours. These incubation conditions are illustrative only, and can be varied as required for the particular assay components and/or desir ed measurement system. Optimization of the incubation conditions for the particular assay components should account for the specific alpha-secretase and/or beta-secretase enzyme used and its pH optimum, any additional enzymes and/or markers that might be used in the assay, and the like. Such optimization is routine and will not require undue experimentation.

[0051] Another exemplary assay utilizes a fusion peptide having maltose binding protein. (MBP) fused to the C-terminal 125 amino acids of APP-S W. The MBP portion is captured on an assay substrate by anti-MBP capture antibody. Incubation of the captured fusion protein in the presence of alpha-secretase and/or beta-secretase results in cleavage of the substrate at the alpha-secretase and/or beta-secretase cleavage sites, respectively. This system can be used to screen for the inhibitory activity of the ageiit(s) of interest. Analysis of the cleavage activity can be, for example, by immunoassay of cleavage products. One such immunoassay detects a unique epitope exposed at the carboxy terminus of the cleaved fusion protein, for example, using the antibody SW192. This assay is described, for example, in US 5,942,400.

[0052] Cellular Assays: Numerous cell-based assays can be used to evaluate the activity of agent(s) of interest on relative alpha-secretase activity to beta-secretase activity and/or processing of APP to release amyloidogenic versus non-amyloidogenic Αβ oligomers.

Contact of an APP substrate with an alpha-secretase and/or beta-secretase enzyme within the cell and in the presence or absence of the agent(s) can be used to demonstrate alpha-secretase promoting and/or beta-secretase inhibitory activity of the agent(s). Preferably, the assay in the presence of the ageni(s) provides at least about 30%, most preferably at least about 50% inhibition of the enzymatic activity, as compared with a non-inhibited control.

[0053] hi one embodiment, cells that naturally express alpha-secretase and/or beta-secretase are used. Alternatively, cells are modified to express a recombinant alpha-secretase and/or

WO 2017/035529

PCT/US2016/049271 beta-secretase or synthetic variant enzymes, as discussed above. The APP substrate may be added to the culturemedium and is preferably expressed, in the cells. Cells that naturally· express APP, variant or mutant forms of APP, or cells transformed to express an isofbrm of APP, unnaut or variant APP. recombinant or t-wtherie APP. APP fragment, or synthetic APP 5 peptide or fosion protein containing the alpha-secretase and/or beta-secretase APP cleavage sites can be used, provided that the expressed APP is permitted to contact the enzyme and enzymatic cleavage activity' can. be analyzed.

[0054] Human cell lines that normally process Αβ from APP provide a usefol means to assay inhibitory activities of the agent(s). Production and release of Αβ and/or other cleavage products into the culture medium can be measured, for example by immunoassay, such as Western blot or enzyme-linked immunoassay (ΕίΑ) such as by ELISA.

[0055] Cells expressing an APP substrate and an active alpha-secretase and/or beta-secretase can be incuba ted in foe presence of the agents to demonstrate relative enzymatic activity’ of the alplia-secretase and/or beta-secretase as compared with a control Relative activity of the 15 alpha-secretase to the beta-secretase can be measured by analysis of one or more cleavage products of the APP substrate. For example, inhibition of beta-secretase activity against, the substrate APP would be expected to decrease release of specific beta-secretase induced APP cleavage products such as Αβ (e.g., Αβ40 or Αβ42), §ΑΡΡβ and APPneo. Promotion or enhancement of alpha-secretase activity against the substrate APP would be expected to 20 increase release of specific alpha-secretase induced APP cleavage products such as sAPPa and p3 peptide.

[0056] Although both neural and non-neural cells process and release Αβ, levels of endogenous beta-secretase activity are low and often difficult to detect by ETA. Tire use of cell types known to have enhanced beta-secretase activity, entranced processing of APP to 25 Αβ, and/or enhanced production of Αβ are therefore preferred. For example, transfection of cells with the Swedish Mutant form of APP (APP-SW): with the Indiana Mutant fonn (APPIN); or with APP-SW-IN provides cells having enhanced beta-secretase activity and producing amounts of Αβ that can be readily' measured.

[0057] In such assay's, for example, the ceils expressing APP, alpha-secretase and/or beta30 seeretase are incubated in a culture medium under conditions suitable for alpha-secretase and/or beta-secretase enzymatic activity at its cleavage site on the APP substrate. On

WO 2017/035529

PCT/US2016/049271 exposure of the cells to the agent(s), the amount of Αβ released into the medium and/or the anionnt of CTF99 fragments of APB in the cell lysates is reduced as compared with the eonhol. Hie cleavage products of APP can be analyzed, for example, by immune reactions •with specific antibodies, as discussed above.

[0058] In certain embodiments, preferred cells for analysis of alpha-secretase -and/or betasecretaxe activity include primary human neuronal cells, primary transgenic annual neuronal ceils where the transgene is APP, and other cells such as those of a stable 293 ceil line expressing APP, for example, APP-SW.

[0059] In Uvo Assays - Animal Models: Various animal models can be used to analyze the activity of agent(s) of interest on relative alpha-secretase and/or beta-secretase activity and/or processing of APP to release Αβ. For example, transgenic animals expressing APP substrate, alpha-secretase andror beta-secretase enzyme can be used to demonstrate inhibitory activity of the agent(s). Certain transgenic animal models have been described, for example, in US 5,877,399; 5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in

Ganes et al. (1995) Nature 373: 523. Preferred are animals that exhibit characteristics associated with the pathophysiology of AD. Administration of the agents) to the transgenic mice described herein provides an alternative method for demonstrating the inhibitory activity of the agent(s). Administr ation of the agent(s) in a pharmaceutically effective carrier and via an administrative route that reaches the tar get tissue in an appropriate therapeutic amount is also preferred.

[0060] Inhibition of beta-secretase mediated cleavage of APP at the beta-secretase cleavage site and of Αβ release can be analyzed in these animals by measure of cleavage fragments in the animal’s body fluids such as cerebral fluid or tissues. Likewise, promotion or enhancement of alpha-secretase mediated cleavage of APP at the alpha-secretase cleavage site and of release of sAPPa can be analyzed in these annuals by measure of cleavage fragments in the animal’s body fluids such as cerebral fluid or tissues, hr certain embodiments, analysis of brain tissues for Αβ deposits or plaques is preferred.

[0061] On contacting an APP substrate with an alpha-secretase and/or beta-secretase enzyme in tire presence of tire agent(s) under conditions sufficient to permit enzymatic mediated cleavage of APP and/or release of Αβ from the substrate, desir able agent(s) are effective to reduce beta-secretase-mediated cleavage of APP at the beta-secretase cleavage site and/or

WO 2017/035529

PCT/US2016/049271 effective to reduce released amounts of Αβ. The agent(s) are also preferably effective to enhance alpha-seeretase-mediated cleavage of API? at the alpha-secretase cleavage site and to increase released amounts of sAPPu. Where, such contacting is the administration of the agent(s) to an anirnal model, for example, as described above, the agent(s) is effective to 5 reduce Αβ deposition in brain tissues of the annual, and to reduce the number and/or size of beta amyloid plaques, Where .such administration is to a human subject, the agent(s) is effective to inhibit or slow fee progression of disease characterized by enhanced amounts of Αβ, to slow the progression of AD in the, and/or to prevent onset or development of AD in a patient at risk for the disease.

[0062] Using the experimental conditions and parameters as described above, the inventors investigated the effects of contemplated compounds on BACE activity with respect to IC50 values, preference towards APP, and various pharmacokinetic parameters in various in vitro and m vivo experiments. Most notably, many of the compounds had submicromolar IC50 values, exhibited pronounced preference towards APP in BACE inhibition, and were able to cross the blood brain barrier in pharmacologically meaningful quantities. Table 1 and Table 2 below list exemplarily results for selected compounds presented herein.

WO 2017/035529

PCT/US2016/049271

F AH #	Structure	MW	CLOgP	Primary
8ACE11C50
3	₌ X)=^>: T R _fa_f	3813	134	0.53uM
	x>° M X^x> 1 .- j-	363.33	12
	-v- J XX ’ Λ	377,36	163	H
	V,. +...../ fei - 'j ?·'· '••F	379.79	174	IM
	-R. M 1 ^ρ-<χχ X'X XX	397.78	185	0.57
	«X .ri . -^?x·. ..R · ' x.^	359.37	3.51	I··
	... xV 33' > * \\ -l· X / x- /’ >:: ^s ‘ J. F-· ·?	413.34	3.96	XX
	' X kc-kX xx. \...,· /' o	385.8
	,/ _FX	379.4	3.41
	f _vr5 X-z' tR >”% T >7 .O -+.	422.4	3.78

Table 1

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/049271

FAH#

Secondary (1st test, n-3)

sAPPalpha

sAPPbeta

sAPP(a/£)

Abera 1-42 sAPP

α/Αβ APR Kd

ill II

T>io%

T>20%

+ «50%

T>20% +>5ff

J6 ~ 03uM

H

III

IMIIi·

W» +

t>10%

+ <50%

f|« T&A

II

1

HI

Mill tsa

»10%

T>20%

+ ==50%

T>20% + >4O

% ISA

111

1

Illi

Mil tsa

B

S·!

T>20% +.>4fr

& ΤδΑ

B

U

B

+>100%

T>30% +>50

%

liii

1

IMI

1

ImmIi

Table 1 (continued)

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

	'i^f>- 7¾. F ^F	347.32	0,98
	<>° O' f z-X	364.33	2.16
	H;.V xf C^Q yx.	336.3	161
	v n.	439 44	4.62
	y w X .Λ	389.4	3.01
	“ΎΖ to. F-J-F	364.33	2.3
	,n '9%t A.	360.13	2.23
	-- ^z _fa_f	376.36	2.19
	<*-A· ./ ~'·· A.	390.4	2.21
	H,N </ x>° Orn '’-v.--- X__.V _FX_F	397.42	2.41
h	“to VRi. χ·	480.46	2.62	0.6

Table 2

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/049271

1		I			Η
				t>40%

	........
1		Ml			Ml
	ellb	H	mi·	t>40%
t>10%	i*·	LfcJ
t>10%	«fee	L»sJ	iilie
			ψ<10%

		iiii/ii		[\|Ι·ΙΙΙ

Table 2 (continued) [0001] More particularly, Figure 1A shows the structures for FAH17 and FAH32, which were tested in an in vitro BACE inhibition assay along with two other compounds, FAH37 and FAH42 (for structures, see Figure 2A and Table 2, respectively). As can be readily seen

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271 from Figure IB, FAH32 had significantly reduced IC50 in the BACE assay. When tested with CHO-7W cells that were stably transfected with human APP (wildtype), Αβ1-42 peptide formation was substantially reduced using FAH32 versus control and FAH17 as shown in Figure IC. On the other hand, FAH32 increased sAPPa formation as compared to FAH17, indicating a higher selectivity of FAH32 towards APP, while sΑΡΡβ formation was reduced as compared to FAH17 as can be seen from Figure ID.

[0002] When compared with FAH37 as shown in Figure 2A, FAH37 was less effective in reducing BACE activity in vitro as shown in Figure 2B, and similar differences in inhibition were also evident from a P5-P5’ fluorescence assay in vitro as is shown in Figure 2C.Further compounds were evaluated and selected compounds are shown in Figure 3A with test results for a BACE activity assay shown in Figure 3B. Notably, even relatively moderate changes in structure resulted in substantial differences in observed BACE activity. These compounds were further tested for selectivity or preference towards APP in a cell based model, and the results are shown for 8ΑΡΡβ production in Figure 3C, for sAPPa in Figure 3D, and for Αβ1-42 production in Figure 3E.

[0003] Table 3 exemplarily shows further physical and pharmacokinetic data for selected compounds according to the inventive subject matter.

FAH32 > FAH17> FAH44 > FAH62 > FAH46 » FAH37

I · $ V-i 3 W S /V V--. Un I s ,·. SI _rA_s ’V ^! f J ξ	W, J \ Ί f / 0 A-	f.) ¥ >0 I / '% ¥ K Ϊ rL	^!! y=0 II 1 / \\ T H HA I i F ' A	^Η·^?Ν v,.N Il Ao AXl· VQ F / C A F F	J >0 n'NZ >·—\ s ¥ U i ^F ’ 9 §

I ~ e.osuM	” O.lpM	“ 0,25μΜ	“ 0.6μΜ	” 1.2μΜ	~5<3 μΜ \|
\| MW:
I 422	353	339	388	364	384 j
\| Sol: good	med	med	excellent	good	good
\| brain ξ ..... - 1 IQ mg/kg SQ: ξ [ < 0.02 ί ' J J J J J ξ	~03 μΜ χικοκικιχικοηηηηΝοηΝοηηΝοηκοΝ	“0.2 pM cwKawwmwoniONOiONonNOioxoi	TBD XWOWWOWOnWOiKOiOXOiONOnNON	0.3 μΜ 1.3 μΜ @30 mi iwwowoxwKowoKonxoioxonxoiOi	~0.ll IIP) nwwwKowoxwKwonKOi«oioxonxoio8

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

Table 3 [0004] Pharmacokinetic data for selected compounds of Table 3 are shown in Figure 4. As is readily apparent, not all compounds were equally able to cross the blood brain barrier, but most compounds did reach pharmacologically meaningful levels given their low IC50 values. Figure 5A provides a further exemplary compound (FAH65) and Figure 5B depicts dose response data for Αβ1-42 production in a cell based system.. Further shown are effects observed with regard to Αβ1-42 production, 8ΑΡΡβ and sAPPa formation. As can be seen, FAH65 exhibits clear preference towards APP in BACE inhibition, and strongly reduces Αβ1-42 production. Moreover, FAH65 has also desirable pharmacological properties as can be seen from Figure 5C. Here, data are presented for oral and subcutaneous administration (SQ) at dosages of 10- and 30 mg/kg. Values are measured in plasma and brain, and the lower graph shows a magnified scale of the area in the box in the upper graph of Figure 5C. Given the low IC50 value of the compound, it should be appreciated that pharmaceutically meaningful concentrations can be achieved in the brain. Similar results for the compounds of Figures 6A and 7A are presented in Figures 6B and 7B. Once more, it should be noted that these exemplary compounds are preferential towards APP in BACE inhibition as can be taken from the data for Αβ1-42, 8ΑΡΡβ, and sAPPa formation. Similar data are expected for FAH74 as shown in Figure 8, which had a IC50 of 9 nM as determined by an in vitro BACE inhibition assay.

[0005] Additional compounds according to the inventive subject matter and associated data are shown in Table 4 below in which MW indicates molecular weight, cLogP is the partition coefficient (log (c_0Ctane/c_water)), TPSA is total polar surface area, BACE IC50 is in micromolar, and PAMPA is parallel artificial membrane permeability assay.

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

Mams

FAH-S1

FAH-02

FAM-84

Structure ,F ^νγ·,r \

ξ /''•Mk-v.p /

301.30 s 1.63

367.30 ΐ 1.S0

381.33

2.15

367.30

1.80

TPSA

58.69

67.92

8AC£1ICS3 (uM)

2.13

5,2

0.S3

5,7

2.23

3.5

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/049271

FAH-12

FAH-13

FAH-14

j/· ?/

349.31

370.28

337.28

1.66

1.54

1.84

67.92

71.58

58.69

2.60

1.50

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

	ri < J Λ... ..AH _s . V Ύ h / \ o	320.2? 1.08	71.58	2.00 [
FAH-Ιδ	/ ?. X _xYyV	303.2.7 -0.20	84.47	ΐ
FAri-17	„ XV ,-S. ,F ,P Z^ NZ ·· \ / Γ ϊ ί r Λ Αχ Αν ⁸ ; y·' S',x 'ν. Χ<Χ> / \ Μ Ν }r*^\ /1 \? W	363.34 2.05	57.S2	0.15/0.09 -::::::::::::::: 0,37 ::::::::::::::::: 8.78 :::::«:::: 1.3 ::::::::::::::::: 0.82 :::::::::::::::::
FAH-IS	_ν / Αγ⁰ ν ί \ Αν ^*Ά. f \ ζ X. „s' χ ¹ V χ- χ κχ Τί Χχ / > % / Χ_-χ	345.35 ] 1.95	67.32	8.18 ] 8.24 ]

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-19 ϊ

Λ^: ft” i r

¥ /r •X \

,/X vZ>* x j.' π ΐί·^._χ y~'

FAR/Ό ΐ V Ή ΐ ί / '

I Ζ'¥

S χ

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH<27

FAH-B

FAM -24

FAH-25

Κ.'ί x,

377.37

57.92

0,71

V\,, rX .Z''^ss.

X .is

2.SS

0,32

335.30

3S7.78

1.61

2.65

93.95

0,57

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FA.H-32

FAH-33

FAH-30

349.34

FAH-34

080 > 109X15

FAH-31

42243

347.32

393.34

53.70

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-35

FAH-38

W.40

364.33

336.30

382,32

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

1.54

80.81

X/' £

383.40

07.92

FAH-40

369.37

2.05

FAH-41 i-SV

X

439.44

3.46

67.32

FAH-42

FAH-43

412.40

2.21

95.56

2.97 t / '7 \ .

Si •X/\ ^f ,x / 'V

HjN' «

ί x,

X i

χ'Χ

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

PAH-48

FAH-49

FAH-50

FAH-51

83.42

82.42

388.42

385.41

2..13

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-52

FAH-S3

V-.

$ \-N

FAH-55 ( v / .·* x% <

HiN' :Ί

H*

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAR57

FAR-SS

FAR-S3

FAR-®

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-84

»4S i 1.81

3SS.41 i

4W45 ί

402.44 |

494,49 ί

400.42 |

492,49 ί

LB

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAIW

:χ.

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-78	y ”* ν·ς._{ν >s}.-‘ ' ^.-Χχ. •w·-'‘·^χ···'·' ‘χ-·'·^Λ”· ''w·:' ” 'Ν' X'	3S8A8 \| IA7

	y	s
FAB-71	_Λ.χ../	;<i> » •j'X j ->^:.: s,s i s	0.20	122.81
	v χ. .X . Λ ··*· X __	ΐ
	. ’-A	i
FAB-72	,·.'; ,.-Άμ, x S \-Λ * 1 / V·''·.% .... -fe ,+X ... r Λ N. Χχ'ίί'···-·.-. >7 - x / \ ,.y /	X< 42 Ϊ	$ίΛ>3	§3.7.1
	\...../ ^Vws;/
	. + -...+
FAB	.» A, Ά \ / ί Ύ *- + ;; J / +,-· --·..<+ ^.,-++^..+\ /—A X..,.../	421.44 Ϊ	4.8S	07,03	0.07 :
FAM-74	Χ'-'Λχ.,../ # > 1 - is \ ./ X %x X ?«W [i 1 Nx v i λ X >''\ Λ^Α<·. i / '_VX' X_f+ XX $ I· ^z 1 k J ’., %v	4M4S 1	2Χ	S3.71	0.31 ί

SUBSTITUTE SHEET (RULE 26)

WO 2017/035529

PCT/US2016/049271

FAH-75

84.48

FAH-76

445

V<

A, ^5* ' Wi>-

93.10

FAH-77

V-44B

SUBSTITUTE SHEET (RULE 26)

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PCT/US2016/049271

Table 4 [0006] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C .... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

1. A compound having a structure according to Formula I:

wherein Ri is a halogenated heteroaryl;

R3 is H, halogen, or optionally halogenated lower alkyl.

2. The compound of claim 1 wherein the heteroaryl is pyridinyl, pyrimidinyl, or oxazolyl.

3. The compound of any one of the preceding claims wherein R2 is a halogenated alkoxy group.

4. The compound of any one of the preceding claims wherein R3 is H or optionally halogenated lower alkyl.

5. The compound of claim 1 wherein R2 is a halogenated alkoxy group.

6. The compound of claim 1 wherein R3 is H or optionally halogenated lower alkyl.

7. A compound having a structure according to Formula II:

2016311502 15 Apr 2019 wherein R2 is an optionally halogenated lower alkoxy group or an optionally halogenated N-alkylamino group;

R3 is H, halogen, or optionally halogenated lower alkyl; and

R4 is an oxazolyl.

8. The compound of claim 7 wherein R2 is a halogenated alkoxy group.

9. The compound of claim 7 wherein R3 is H or optionally halogenated lower alkyl.

10. The compound of claim 7 wherein R2 is a halogenated alkoxy group.

11. The compound of claim 7 wherein R3 is H.

12. The compound of claim 7 wherein R3 halogenated lower alkyl.

13. The compound according to claim 1 having a structure according to Formula III:

Formula III wherein R2 is an optionally halogenated lower alkoxy group or an optionally halogenated N-alkylamino group;

R3 is H, halogen, or optionally halogenated lower alkyl;

R5 is halogen; and

2016311502 15 Apr 2019

X and Q are independently CH or N and X and Q are not the same.

14. The compound of claim 13 wherein Rs is F.

15. The compound of claim 13 wherein R2 is a halogenated alkoxy group.

16. The compound of claim 13 wherein R3 is H.

17. A compound having a structure according to Formula IV:

18. A compound having a structure according to Formula V:

19. A compound having a structure according to Formula VI or XIII:

2016311502 15 Apr 2019

Formula XIII.

20. A compound having a structure according to Formula VII:

Formula VII.

21. A compound having a structure according to Formula VIII:

22. A compound having a structure according to Formula IX:

2016311502 15 Apr 2019

23. A compound having a structure according to Formula X:

Formula X

24. A compound having a structure according to Formula XI:

Formula XI.

25. A compound having a structure according to Formula XII:

2016311502 26 Jun 2019

Formula XII.

26. A pharmaceutical composition comprising a compound according to any one of claims 1-25 in combination with a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 26 wherein the compound is present in an amount effective to inhibit BACE in a patient when administered to the patient.

28. The pharmaceutical composition of claim 26 or claim 27 wherein the composition is formulated for oral administration or injection.

29. The pharmaceutical composition of claim 26 further comprising a second pharmaceutical agent suitable for treatment of a neurological condition.

30. The pharmaceutical composition of claim 29 wherein the neurological condition is Alzheimer’s Disease.

31. Use of a compound according to any one of claims 1-25 in the manufacture of a medicament.

32. The use of claim 31 wherein the medicament is for reduction of BACE activity in a patient.

33. Use of a compound according to any one of claims 1-25 for the treatment of Alzheimer’s Disease.

34. Use of a compound according to any one of claims 1-25 to reduce BACE activity.

35. The use of claim 34 wherein the reduction of BACE activity is in vivo.

2016311502 26 Jun 2019

36. A method of treating a patient diagnosed with Alzheimer’s Disease or at risk for disease progression of mild cognitive decline, comprising a step of administering to the patient in need thereof a pharmaceutical composition comprising a compound according to any one of claims 1-25 in an amount effective to treat the patient.

37. The method of claim 36 wherein the amount effective is an amount that reduces BACE activity in vivo when the pharmaceutical composition is administered to the patient.

38. A method of reducing BACE activity, comprising contacting BACE with a compound according to any one of claims 1-25.

39. The method of claim 38 wherein the compound has an IC50 of less than 1 μΜ.

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Patent Attorneys for the Applicant/Nominated Person

SPRUSON & FERGUSON